Advertisement

Altered apolipoprotein C expression in association with cognition impairments and hippocampus volume in schizophrenia and bipolar disorder

  • Christian KnöchelEmail author
  • Jonathan Kniep
  • Jason D. Cooper
  • Michael Stäblein
  • Sofia Wenzler
  • Jan Sarlon
  • David Prvulovic
  • David E. J. Linden
  • Sabine Bahn
  • Pawel Stocki
  • Sureyya Ozcan
  • Gilberto Alves
  • Andre F. Carvalho
  • Andreas Reif
  • Viola Oertel-Knöchel
Original Paper

Abstract

Proteomic analyses facilitate the interpretation of molecular biomarker probes which are very helpful in diagnosing schizophrenia (SZ). In the current study, we attempt to test whether potential differences in plasma protein expressions in SZ and bipolar disorder (BD) are associated with cognitive deficits and their underlying brain structures. Forty-two plasma proteins of 29 SZ patients, 25 BD patients and 93 non-clinical controls were quantified and analysed using multiple reaction monitoring-based triple quadrupole mass spectrometry approach. We also computed group comparisons of protein expressions between patients and controls, and between SZ and BD patients, as well. Potential associations of protein levels with cognitive functioning (psychomotor speed, executive functioning, crystallised intelligence) as well as underlying brain volume in the hippocampus were explored, using bivariate correlation analyses. The main finding of this study was that apolipoprotein expression differed between patients and controls and that these alterations in both disease groups were putatively related to cognitive impairments as well as to hippocampus volumes. However, none of the protein level differences were related to clinical symptom severity. In summary, altered apolipoprotein expression in BD and SZ was linked to cognitive decline and underlying morphological changes in both disorders. Our results suggest that the detection of molecular patterns in association with cognitive performance and its underlying brain morphology is of great importance for understanding of the pathological mechanisms of SZ and BD, as well as for supporting the diagnosis and treatment of both disorders.

Keywords

APOC MRM SMRT Psychosis spectrum Bipolar Schizophrenia Proteomics 

Notes

Acknowledgments

MRI was performed at the Frankfurt Brain Imaging Centre, supported by the German Research Council (DFG) and the German Ministry for Education and Research (BMBF; Brain Imaging Center Frankfurt/Main, DLR 01GO0203). We acknowledge the Brazilian National Council of Research (CNPq) for funding Dr. Gilberto Alves, who is supported by a postdoctoral scholarship from the CNPq (Process 209981/2013-0) in an exchange cooperation programme with the Goethe University, Frankfurt am Main, Germany, and Dr. Andre F Carvalho, who receives CNPq research fellowship awards (level II). Sabine Bahn is a Director, and Jason D. Cooper and Sureyya Ozcan are consultants of Psynova Neurotech. None of the other authors report any conflict of interest. Jason Cooper, Sabine Bahn and Sureyya Ozcan would like to thank the Stanley Medical Research Institute for centre support. The study was reviewed and approved by the ethics committee of the Faculty of medicine, Goethe University, Frankfurt/Main, Germany.

Compliance with ethical standards

Conflict of interest

None.

References

  1. 1.
    Ali IM (1998) Long-term treatment with antidepressants in primary care. Are sub-therapeutic doses still being used? Psychiatr Bull 22:15–19CrossRefGoogle Scholar
  2. 2.
    Almeida JR, Mechelli A, Hassel S, Versace A, Kupfer DJ, Phillips ML (2009) Abnormally increased effective connectivity between parahippocampal gyrus and ventromedial prefrontal regions during emotion labeling in bipolar disorder. Psychiatry Res 30:195–201CrossRefGoogle Scholar
  3. 3.
    Alsaif M, Guest PC, Schwarz E, Reif A, Kittel-Schneider S, Spain M, Rahmoune H, Bahn S (2012) Analysis of serum and plasma identifies differences in molecular coverage, measurement variability, and candidate biomarker selection. Proteomics Clin Appl 6:297–303CrossRefPubMedGoogle Scholar
  4. 4.
    APA (1994) Diagnostic and statistical manual of mental disorders, 4th edn. American Psychiatric Association, Washington, DCGoogle Scholar
  5. 5.
    Avery SN, Williams LE, Woolard AA, Heckers S (2013) Relational memory and hippocampal function in psychotic bipolar disorder. Eur Arch Psychiatry Clin NeurosciGoogle Scholar
  6. 6.
    Bech P (1981) Rating scales for affective disorders: their validity and consistency. Acta Psychiatr Scand 295:1–101Google Scholar
  7. 7.
    Choi M, Chang CY, Clough T, Broudy D, Killeen T, MacLean B, Vitek O (2014) MSstats: an R package for statistical analysis of quantitative mass spectrometry-based proteomic experiments. Bioinformatics 30:2524–2526CrossRefPubMedGoogle Scholar
  8. 8.
    Craddock N, Owen MJ (2005) The beginning of the end for the Kraepelinian dichotomy. Br J Psychiatry 186:364–366CrossRefPubMedGoogle Scholar
  9. 9.
    Dassati S, Waldner A, Schweigreiter R (2014) Apolipoprotein D takes center stage in the stress response of the aging and degenerative brain. Neurobiol Aging 35:1632–1642CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    de Witte L, Tomasik J, Schwarz E, Guest PC, Rahmoune H, Kahn RS, Bahn S (2014) Cytokine alterations in first-episode schizophrenia patients before and after antipsychotic treatment. Schizophr Res 154:23–29CrossRefPubMedGoogle Scholar
  11. 11.
    Dean B, Digney A, Sundram S, Thomas E, Scarr E (2008) Plasma apolipoprotein E is decreased in schizophrenia spectrum and bipolar disorder. Psychiatry Res 158:75–78CrossRefPubMedGoogle Scholar
  12. 12.
    Deichmann R, Schwarzbauer C, Turner R (2004) Optimisation of the 3D MDEFT sequence for anatomical brain imaging: technical implications at 1.5 and 3 T. NeuroImage 21:757–767CrossRefPubMedGoogle Scholar
  13. 13.
    Digney A, Keriakous D, Scarr E, Thomas E, Dean B (2005) Differential changes in apolipoprotein E in schizophrenia and bipolar I disorder. Biol Psychiatry 57:711–715CrossRefPubMedGoogle Scholar
  14. 14.
    Ehrlich S, Brauns S, Yendiki A, Ho BC, Calhoun V, Schulz SC, Gollub RL, Sponheim SR (2011) Associations of cortical thickness and cognition in patients with schizophrenia and healthy controls. Schizophr Bull 38(5):1050–1062. doi: 10.1093/schbul/sbr018 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Elliott DA, Weickert CS, Garner B (2010) Apolipoproteins in the brain: implications for neurological and psychiatric disorders. Clin Lipidol 51:555–573CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Ellison-Wright I, Bullmore E (2010) Anatomy of bipolar disorder and schizophrenia: a meta-analysis. Schizophr Res 117:1–12CrossRefPubMedGoogle Scholar
  17. 17.
    Enaw JO, Smith AK (2013) Biomarker development for brain-based disorders: recent progress in psychiatry. J Neurol Psychol 1:7PubMedPubMedCentralGoogle Scholar
  18. 18.
    Gagliardi L, Ho JT, Torpy DJ (2010) Corticosteroid-binding globulin: the clinical significance of altered levels and heritable mutations. Mol Cell Endocrinol 316(1), pp. 24–34, doi: 10.1016/j.mce.2009.07.015 CrossRefPubMedGoogle Scholar
  19. 19.
    Gibbons AS, Thomas EA, Scarr E, Dean B (2010) Low Density lipoprotein receptor-related protein and apolipoprotein e expression is altered in schizophrenia. Front Psychiatry 1:19PubMedPubMedCentralGoogle Scholar
  20. 20.
    Gupta CN, Calhoun VD, Rachakonda S, Chen J, Patel V, Liu J, Segall J, Franke B, Zwiers MP, Arias-Vasquez A, Buitelaar J, Fisher SE, Fernandez G, van Erp TG, Potkin S, Ford J, Mathalon D, McEwen S, Lee HJ, Mueller BA, Greve DN, Andreassen O, Agartz I, Gollub RL, Sponheim SR, Ehrlich S, Wang L, Pearlson G, Glahn DC, Sprooten E, Mayer AR, Stephen J, Jung RE, Canive J, Bustillo J, Turner JA (2015) Patterns of gray matter abnormalities in schizophrenia based on an international mega-analysis. Schizophr Bull 41:1133–1142CrossRefPubMedGoogle Scholar
  21. 21.
    Gutierrez-Galve L, Bruno S, Wheeler-Kingshott CA, Summers M, Cipolotti L, Ron MA (2011) IQ and the fronto-temporal cortex in bipolar disorder. J Int Neuropsychol Soc 18:370–374CrossRefGoogle Scholar
  22. 22.
    Hall MH, Levy DL, Salisbury DF, Haddad S, Gallagher P, Lohan M, Cohen B, Ongür D, Smoller JW (2014) Neurophysiologic effect of GWAS derived schizophrenia and bipolar risk variants. Am J Med Genet B Neuropsychiatr Genet 165B(1):9–18CrossRefPubMedGoogle Scholar
  23. 23.
    Hartberg CB, Lawyer G, Nyman H, Jonsson EG, Haukvik UK, Saetre P, Bjerkan PS, Andreassen OA, Hall H, Agartz I (2010) Investigating relationships between cortical thickness and cognitive performance in patients with schizophrenia and healthy adults. Psychiatry Res 182:123–133CrossRefPubMedGoogle Scholar
  24. 24.
    Hartberg CB, Student K, Rimol LM, Haukvik UK, Lange EH, Nesvåg R, Dale AM, Melle I, Andreassen OA, Agartz I (2011) Brain cortical thickness and surface area correlates of neurocognitive performance in patients with schizophrenia, bipolar disorder, and healthy adults. J Int Neuropsychol Soc 17:1080–1093CrossRefPubMedGoogle Scholar
  25. 25.
    Hautzinger M, Keller F, Kühner C (2006) Das Beck Depressionsinventar II. Deutsche Bearbeitung und Handbuch zum BDI II. Harcourt Test Services, Frankfurt am MainGoogle Scholar
  26. 26.
    Huang Y, Mahley RW (2014) Apolipoprotein E: structure and function in lipid metabolism, neurobiology, and Alzheimer's diseases. Neurobiol Dis 72 (Pt A):3–12. doi: 10.1016/j.nbd.2014.08.025
  27. 27.
    Hwang Y, Kim J, Shin JY, Kim JI, Seo JS, Webster MJ, Lee D, Kim S (2013) Gene expression profiling by mRNA sequencing reveals increased expression of immune/inflammation-related genes in the hippocampus of individuals with schizophrenia. Transl Psychiatry 3:e321CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Kashuba E, Bailey J, Allsup D, Cawkwell L (2013) The kinin-kallikrein system: physiological roles, pathophysiology and its relationship to cancer biomarkers. Biomarkers 18(4):279–296. doi: 10.3109/1354750X.2013.787544 CrossRefPubMedGoogle Scholar
  29. 29.
    International Schizophrenia Consortium, Purcell SM, Wray NR, Stone JL, Visscher PM, O’Donovan MC, Sullivan PF, Sklar P (2009) Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460:748–752PubMedCentralGoogle Scholar
  30. 30.
    Kay SR, Fiszbein A, Opler LA (1987) The Positive And Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr Bull 13:261–276CrossRefPubMedGoogle Scholar
  31. 31.
    Kim DH, Yeo SH, Park JM, Choi JY, Lee TH, Park SY, Ock MS, Eo J, Kim HS, Cha HJ (2014) Genetic markers for diagnosis and pathogenesis of Alzheimer’s disease. Gene 545(2):185–193CrossRefPubMedGoogle Scholar
  32. 32.
    Knöchel C, Stablein M, Storchak H, Reinke B, Jurcoane A, Prvulovic D, Linden DE, van de Ven V, Ghinea D, Wenzler S, Alves G, Matura S, Kroger A, Oertel-Knochel V (2014) Multimodal assessments of the hippocampal formation in schizophrenia and bipolar disorder: evidences from neurobehavioral measures and functional and structural MRI. Neuroimage Clin 6:134–144CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Knöchel C, Reuter J, Reinke B, Stäblein M, Marbach K, Feddern R, Kuhlmann K, Alves G, Prvulovic D, Linden DE, Oertel-Knochel V (2016) Overlapping cortical thinning in bipolar disorder and schizophrenia. Schizophr Res 172(1–3):78–85CrossRefPubMedGoogle Scholar
  34. 34.
    Kraepelin E (1896) Psychiatrie. - Ein Lehrbuch für Studierende und Ärzte. 5., vollst. umgearb. Aufl. Leipzig BarthGoogle Scholar
  35. 35.
    Lehrl S (2005) Mehrfachwahl–Wortschatz-Intelligenztest M–W-T B. Spitta Verlag GmbH, GöttingenGoogle Scholar
  36. 36.
    Levin Y, Schwarz E, Wang L, Leweke FM, Bahn S (2007) Label-free LC–MS/MS quantitative proteomics for large-scale biomarker discovery in complex samples. J Sep Sci 30:2198–2203CrossRefPubMedGoogle Scholar
  37. 37.
    Maldjian JA, Laurienti PJ, Burdette JB, Kraft RA (2003) An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets. Neuroimage 19:1233–1239CrossRefPubMedGoogle Scholar
  38. 38.
    Martins-De-Souza D, Wobrock T, Zerr I, Schmitt A, Gawinecka J, Schneider-Axmann T, Falkai P, Turck CW (2010) Different apolipoprotein E, apolipoprotein A1 and prostaglandin-H2 D-isomerase levels in cerebrospinal fluid of schizophrenia patients and healthy controls. World J Biol Psychiatry 11:719–728CrossRefPubMedGoogle Scholar
  39. 39.
    Oertel-Knöchel V, Knochel C, Rotarska-Jagiela A, Reinke B, Prvulovic D, Haenschel C, Hampel H, Linden DE (2012) Association between psychotic symptoms and cortical thickness reduction across the schizophrenia spectrum. Cereb Cortex 23(1):61–70CrossRefPubMedGoogle Scholar
  40. 40.
    Meyer JM, Davis VG, Goff DC, McEvoy JP, Nasrallah HA, Davis SM, Rosenheck RA, Daumit GL, Hsiao J, Swartz MS, Stroup TS, Lieberman JA (2008) Change in metabolic syndrome parameters with antipsychotic treatment in the CATIE schizophrenia trial: prospective data from phase 1. Schizophr Res 101:273–286CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Nascimento JM, Martins-de-Souza DNPJ (2015) The proteome of schizophrenia. Schizophr 4(1):14003Google Scholar
  42. 42.
    O’Donnell BF, Vohs JL, Hetrick WP, Carroll CA, Shekhar A (2004) Auditory event-related potential abnormalities in bipolar disorder and schizophrenia. Int J Psychophysiol 53:45–55CrossRefPubMedGoogle Scholar
  43. 43.
    Oertel-Knöchel V, Knochel C, Rotarska-Jagiela A, Reinke B, Prvulovic D, Haenschel C, Hampel H, Linden DE (2012) Association between psychotic symptoms and cortical thickness reduction across the schizophrenia spectrum. Cereb CortexGoogle Scholar
  44. 44.
    Padrao AI, Ferreira R, Vitorino R, Amado F (2012) Proteome-base biomarkers in diabetes mellitus: progress on biofluids’ protein profiling using mass spectrometry. Proteomics Clin Appl 6:447–466CrossRefGoogle Scholar
  45. 45.
    R Core Team (2014) R: a language and environment for statistical computing. R Foundation for Statistical Computing, ViennaGoogle Scholar
  46. 46.
    Ramachandran S, Venugopal A, Sathisha K, Reshmi G, Charles S, Divya G, Chandran NS, Mullassari A, Pillai MR, Kartha CC (2012) Proteomic profiling of high glucose primed monocytes identifies cyclophilin A as a potential secretory marker of inflammation in type 2 diabetes. Proteomics 12:2808–2821CrossRefPubMedGoogle Scholar
  47. 47.
    Reitan RM, Hom J, Wolfson D (1988) Verbal processing by the brain. J Clin Exp Neuropsychol 10:400–408CrossRefPubMedGoogle Scholar
  48. 48.
    Sadler NC, Angel TE, Lewis MP, Pederson LM, Chauvigne-Hines LM, Wiedner SD, Zink EM, Smith RD, Wright AT (2012) Activity-based protein profiling reveals mitochondrial oxidative enzyme impairment and restoration in diet-induced obese mice. PLoS One 7:e47996CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Schaefer TL, Grace CE, Braun AA, Amos-Kroohs RM, Graham DL, Skelton MR, Williams MT, Vorhees CV (2013) Cognitive impairments from developmental exposure to serotonergic drugs: citalopram and MDMA. Int J Neuropsychopharmacol 16(6):1383–1394CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Sanchez-Morla EM, Garcia-Jimenez MA, Barabash A, Martinez-Vizcaino V, Mena J, Cabranes-Diaz JA, Baca-Baldomero E, Santos JL (2008) P50 sensory gating deficit is a common marker of vulnerability to bipolar disorder and schizophrenia. Acta Psychiatr Scand 117:313–318CrossRefPubMedGoogle Scholar
  51. 51.
    Sasaki J, Funakoshi M, Arakawa K (1985) Lipids and apolipoproteins in patients treated with major tranquilizers. Clin Pharmacol Ther 37:684–687CrossRefPubMedGoogle Scholar
  52. 52.
    Schwarz E, Izmailov R, Spain M, Barnes A, Mapes JP, Guest PC, Rahmoune H, Pietsch S, Leweke FM, Rothermundt M, Steiner J, Koethe D, Kranaster L, Ohrmann P, Suslow T, Levin Y, Bogerts B, van Beveren NJ, McAllister G, Weber N, Niebuhr D, Cowan D, Yolken RH, Bahn S (2010) Validation of a blood-based laboratory test to aid in the confirmation of a diagnosis of schizophrenia. Biomark Insights 5:39–47PubMedPubMedCentralGoogle Scholar
  53. 53.
    Schwarz E, Guest PC, Rahmoune H, Harris LW, Wang L, Leweke FM, Bahn S (2012) Identification of a biological signature for schizophrenia in serum. Mol Psychiatry 17:494–502CrossRefPubMedGoogle Scholar
  54. 54.
    Serra-Grabulosa JM, Salgado-Pineda P, Junque C, Sole-Padulles C, Moral P, Lopez-Alomar A, Lopez T, Lopez-Guillen A, Bargallo N, Mercader JM, Clemente IC, Bartres-Faz D (2003) Apolipoproteins E and C1 and brain morphology in memory impaired elders. Neurogenetics 4:141–146PubMedGoogle Scholar
  55. 55.
    Shenton ME, Dickey CC, Frumin M, McCarley RW (2001) A review of MRI findings in schizophrenia. Schizophr Res 49:1–52CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Smith RC, Segman RH, Golcer-Dubner T, Pavlov V, Lerer B (2008) Allelic variation in ApoC3, ApoA5 and LPL genes and first and second generation antipsychotic effects on serum lipids in patients with schizophrenia. Pharmacogenomics J 8:228–236CrossRefPubMedGoogle Scholar
  57. 57.
    Smith MJ, Barch DM, Csernansky JG (2009) Bridging the gap between schizophrenia and psychotic mood disorders: relating neurocognitive deficits to psychopathology. Schizophr Res 107:69–75CrossRefPubMedGoogle Scholar
  58. 58.
    Song X, Li X, Gao J, Zhao J, Li Y, Fan X, Lv L (2014) APOA-I: a possible novel biomarker for metabolic side effects in first episode schizophrenia. PLoS One 9:e93902CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Takahashi S, Cui Y, Han Y, Fagerness JA, Galloway B, Shen Y, Kojima T, Uchiyama M, Faraone SV, Tsuang MT (2008) Association of SNPs and haplotypes in APOL1, 2 and 4 with schizophrenia. Schizophr Res 104(1–3):153–164CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Verbrugghe P, Bouwer S, Wiltshire S, Carter K, Chandler D, Cooper M, Morar B, Razif MF, Henders A, Badcock JC, Dragovic M, Carr V, Almeida OP, Flicker L, Montgomery G, Jablensky A, Kalaydjieva L (2012) Impact of the Reelin signaling cascade (ligands–receptors–adaptor complex) on cognition in schizophrenia. Am J Med Genet B Neuropsychiatr Genet 159B:392–404CrossRefPubMedGoogle Scholar
  61. 61.
    Vila-Rodriguez F, Honer WG, Innis SM, Wellington CL, Beasley CL (2011) ApoE and cholesterol in schizophrenia and bipolar disorder: comparison of grey and white matter and relation with APOE genotype. J Psychiatry Neurosci 36:47–55CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Wang PS, Insel TR (2010) NIMH-funded pragmatic trials: moving on. Neuropsychopharmacology 35(13):2489–2490CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Wesseling H, Gottschalk MG, Bahn S (2014) Targeted multiplexed selected reaction monitoring analysis evaluates protein expression changes of molecular risk factors for major psychiatric disorders. Int J Neuropsychopharmacol 18(1)Google Scholar
  64. 64.
    Wittchen H-U, Zaudig M, Fydrich T (1997) Strukturiertes Klinisches Interview für DSM-IV. Hogrefe, GöttingenGoogle Scholar
  65. 65.
    Woods S (2003) Chlorpromazine equivalent doses for the newer atypical antipsychotics. J Clin Psychiatry 64:663–667CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Christian Knöchel
    • 1
    Email author
  • Jonathan Kniep
    • 1
  • Jason D. Cooper
    • 2
  • Michael Stäblein
    • 1
    • 3
  • Sofia Wenzler
    • 1
    • 3
  • Jan Sarlon
    • 1
  • David Prvulovic
    • 1
  • David E. J. Linden
    • 4
  • Sabine Bahn
    • 2
  • Pawel Stocki
    • 2
    • 6
  • Sureyya Ozcan
    • 2
  • Gilberto Alves
    • 5
  • Andre F. Carvalho
    • 5
  • Andreas Reif
    • 1
  • Viola Oertel-Knöchel
    • 1
  1. 1.Laboratory for Neuroimaging, Department of Psychiatry, Psychosomatic Medicine and PsychotherapyGoethe UniversityFrankfurt am MainGermany
  2. 2.Institute of BiotechnologyUniversity of CambridgeCambridgeUK
  3. 3.Brain Imaging CentreGoethe UniversityFrankfurt am MainGermany
  4. 4.MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Institute of Psychological Medicine and Clinical NeurosciencesCardiff UniversityCardiffUK
  5. 5.Translational Psychiatry Research Group, Department of Clinical Medicine, Faculty of MedicineFederal University of CearaFortalezaBrazil
  6. 6.Psynova Neurotech LtdCambridgeUK

Personalised recommendations